A Switchable Palladium(II) Trefoil Entangled Tetrahedron with Temperature Dependence and Concentration Independence

Abstract Self‐assembly makes metallo‐interlocked architectures attractive targets, but being in equilibrium with smaller species means that they can suffer from dilution effects. We show that a junctioned system gives rise to a [Pd4(L)2]8+ trefoil entangled tetrahedron irrespective of concentration. Heating the sample reversibly shifts the equilibrium from the knot to an isomeric non‐interlocked dual metallo‐cycle, demonstrating that thermodynamic equilibria can still be exploited for switching even in the absence of concentration effects.


2
A suspension of 1 (1.30 g, 5.28 mmol) and HClaq (40 mL, 6 M) was stirred in an ice bath. Sodium nitrite (0.728 g, 10.6 mmol) in water (4 mL) was added dropwise with stirring. After five minutes, sodium azide (0.686 g, 10.6 mmol) in water (4 mL) was added dropwise with stirring. After one hour, the mixture was neutralised with NaHCO3 and the aqueous phase was extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with water (50 mL) and the solvent removed under vacuum. The residue was dissolved in 4:1 DMF/water (25 mL) and to this was added 2-(2-methyl-2'hydroxy-1-butynyl)-6-(2-(trimethylsilyl)ethynyl)-pyridine [1] (1.77 g, 6.86 mmol), sodium carbonate (1.45 g, 13.7 mmol), CuSO45H2O (0.527 g, 2.11 mmol) and sodium ascorbate (0.836 g, 4.22 mmol). After stirring at room temperature overnight, DCM (100 mL) and EDTA/NH4OHaq (0.1 M, 100 mL) were added and the mixture was stirred vigorously for one hour. The layers were separated and the aqueous phase was extracted with DCM (2 x 40 mL). The combined organic layers were washed with water (5 x 100 mL) then with brine (50 mL) and the solvent removed under vacuum. Column chromatography (eluting with acetone/DCM, gradient 1:4 v/v to neat acetone) gave the product as a pale brown solid. Yield: 1.92 g (80%). 1    PART B: Ethylene glycol monomethyl tosylate [2] (0.151 g, 0.655 mmol) and sodium azide (0.0461 g, 0.710 mmol) were combined in 4:1 DMF/water (3 mL) and were heated at 110 °C for one hour with stirring. The resulting mixture was added to the residue from Part A along with CuSO45H2O (0.0545 g, 0.218 mmol) and sodium ascorbate (0.0865 g, 0.437 mmol) and additional DMF/water (4:1 v/v, 3 mL). The mixture was heated at 50 °C overnight. DCM (100 mL) and EDTA/NH4OH (0.1 M, 100 mL) were added and the mixture was stirred vigorously for one hour. The layers were separated and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organic layers were washed with water (50 mL), dried over Na2SO4, filtered and the solvents were removed under reduced pressure. The residue was purified by column chromatography (eluting with DCM/acetone, gradient neat DCM to DCM/acetone 2:1) to give the desired product as an off-white solid after removal of solvent. Yield: 0.207 g (75%). 1 13

L-4PEG
PART A: A combination of 2 (0.145 g, 0.317 mmol) and sodium hydroxide (0.032 g, 0.79 mmol) in toluene (8 mL) was refluxed for 80 minutes. The solution was filtered through cotton wool, and the solvent was removed under vacuum. The residue was passed through a silica plug (eluting with acetone) and the solvent removed under vacuum. The mass of the residue was 0.089 g.
PART B: Tetraethylene glycol ditosylate [3] (0.053 g, 0.11 mmol) and sodium azide (0.014 g, 0.22 mmol) were combined in DMF (1 mL) and were heated at 110 °C for one hour with stirring. The resulting mixture was added to the residue from Part A along with CuSO45H2O (0.013 g, 0.053 mmol) and sodium ascorbate (0.021 g, 0.11 mmol) and DMF (6 mL) and water (1 mL). The mixture was heated at 50 °C overnight under N2. DCM (100 mL) and EDTA/NH4OH (0.1 M, 100 mL) were added and the mixture was stirred vigorously for one hour. The organic phase was separated, and the solvent removed under vacuum. The residue was taken up in DCM (100 mL) and washed with water (2 x 100 mL) and the solvent removed under vacuum to give the product as a white solid. Yield: 100 mg (90%).  13

L-6PEG
PART A: A combination of 2 (0.250 g, 0.546 mmol) and sodium hydroxide (0.055 g, 1.4 mmol) in toluene (10 mL) was refluxed for 80 minutes. The solution was filtered through cotton wool, and the solvent was removed under vacuum. The residue was passed through a silica plug (eluting with acetone) and the solvent removed under vacuum. The mass of the residue was 0.160 g.
PART B: Hexaethylene glycol ditosylate [4] (0.113 g, 0.191 mmol) and sodium azide (0.026 g, 0.40 mmol) were combined in DMF (1 mL) and were heated at 110 °C for one hour with stirring. The resulting mixture was added to the residue from PART A along with CuSO45H2O (0.024 g, 0.095 mmol) and sodium ascorbate (0.038 g, 0.19 mmol) and DMF (6 mL) and water (1 mL). The mixture was heated at 50 °C overnight under N2. DCM (100 mL) and EDTA/NH4OH (0.1 M, 100 mL) were added and the mixture was stirred vigorously for one hour. The organic phase was separated, and the solvent removed under vacuum. The residue was taken up in DCM (100 mL) and washed with water (2 x 100 mL) and the solvent removed under vacuum to give the product as a white solid. Yield: 211 mg (98%).         Observed in black, calculated in blue. Note the peak at 385.0561 m/z is derived from cleavage of the substituent of the peripheral triazole, and formation of the associated triazolato species. [5] There is also a peak at 395.0658 (denoted with an asterisk, *) which arises from fragmentation of the peak at 404.4157, which we were unable to conclusively identify.
We utilised MS/MS to probe the origin on the 404.4157 [CYCLE-mono -H] 3+ peak (Figure 1.18), as well as other species.  From the MS/MS we were able to ascertain that the 404.4069 peak was derived from the 411.0725 peak (byproduct of formation: HF) and the 385.0538 peaks was derived from the 404.4069 peak (byproduct of formation CH3OCH2CH2-) and possibly the 411.0725 peak. It also originates from the [CYCLE-mono] 4+ peak. Cleavage of substituents from triazoles for formation of triazalato species is known in the literature. [5]

CAT-mono
In proton labelling for this compound, normal labels (e.g. Ha or a) are the 'outer' environment, labels with a prime symbol (e.g. Ha′ or a′) are the 'inner' environment.     Expressing the reaction as: 2 x CYCLE-mono CAT-mono

DUAL-4PEG
The

TET-6PEG
In proton labelling for this compound, normal labels (e.g. Ha or a) are the 'outer' environment, labels with a prime symbol (e.g. Ha′ or a′) are the 'inner' environment.

DUAL-6PEG
Heating samples of TET-6PEG in [D6]DMSO lead to increased conversion into DUAL-6PEG. The introduction of other solvents (CD3CN or D2O) also increased the relative proportion of DUAL-6PEG.   Expressing the reaction as:

DFT Calculations
Density functional theory (DFT) calculations were performed using the ORCA program version 5.0. [6] Structures were fully optimized using the BP86 functional [7] with C and H atoms treated by the def2-SVP basis set and all other atoms (N, O, Pd) treated by the def2-TZVPP basis set. [8] The resolution of identity approximation was also used with the general auxiliary basis set (def2/J). [9] The Def2-ECP effective core potential was used for Pd [10] and dispersion interactions treated using the D3BJ approach. [11] Structures were optimised with tight convergence criteria on both the geometry and selfconsistent field (SCF) cycles. Numerical frequencies were computed to ensure optimised structures represent local minima and to extract vibrational energies. Solvent effects were considered by computing energy with the Conductor-like Polarizable Continuum Model [12] featuring the COSMO [13] epsilon function using the gas phase optimised structures.
As well as providing structural information, we were able to establish that 1. The two possible conformers for DUAL-6PEG were similar in energy (3 kJ mol -1 ) and so both would exist, with rapid interchange and/or local environment equivalence on the NMR time scale. 2. A trend exists where as the dielectric constant of the solvent increases (gas phase, acetone, acetonitrile, DMSO) the relative favourability of the ravel with respect to DUAL-6PEG increases, in keeping with the experimental data where adding acetonitrile to a DMSO solution of TET-6PEG resulted in increased amounts of DUAL-6PEG. This is presumably due to enhanced screening of repulsive cationic charge and/or greater solvophobicity for aromatic regions.